This protocol continues implementation of a laboratory model to evaluate medications potentially useful in the treatment of cocaine abuse, investigating problems relevant to understanding and reducing uncontrolled cocaine use. Psychiatric comorbidities are pervasive in the cocaine-dependent population, and are significant in the population seen in community treatment centers. However, these comorbidities are rarely addressed in either clinical trials or laboratory settings. While it has been hypothesized that treatment for cocaine dependence could be improved by targeting cocaine users with specific psychiatric comorbidities, this has not been systematically evaluated. We will examine the relationship between psychiatric comorbidity and potential medications for cocaine dependence using two approaches. First, we will compare the subjective and reinforcing effects of cocaine under controlled laboratory conditions, in groups of abstinent cocaine abusers with Major Depressive Disorders (MDD), Attention Deficit/Hyperactivity Disorder (ADHD) or no psychiatric comorbidity. If cocaine use in individuals with comorbid disorders is related to their comorbid. disorder, then the behavioral effects of cocaine should vary across the groups being studied. Second, we will compare responses to cocaine under three separate conditions: maintenance on 1) gabapentin, 2) venlafaxine, and 3) the combination of the two medications. The laboratory, setting of the current proposal offers a unique opportunity to test the hypothesis that individuals with comorbid MDD or ADHD respond differently to cocaine than those without a comorbid psychiatric disorder, and that treating the MDD or ADHD alone will not sufficiently reduce the response to cocaine. Treating the comorbid disorder or decreasing the behavioral effects of cocaine will be necessary but not sufficient pharmacotherapy for individuals with comorbid disorders. A combination of the gabapentin for cocaine and venlafaxine for depressive symptoms will have a synergistic effect in these individuals. The laboratory is an ideal setting in which to carry out this research, allowing us to carefully monitor participants and collect maximal data with the fewest number of participants. The proposed research offers a unique opportunity to evaluate medications in cocaine-dependent individuals with MDD, ADHD or no comorbid disorder, and will provide important information about differential responses of these groups to cocaine and to gabapentin and venlafaxine, alone and in combination.